TYRO3, AXL and MER (TAM) receptors are protein tyrosine kinases (PTK) that regulate several immune responses [
82], in particular the clearance of apoptotic cells and the inhibition of innate immunity [
83,
84]. TYRO3 is essentially found in the central nervous system, while MER and AXL are broadly expressed and can be found on APCs, such as monocytes and macrophages [
85]. TAM receptors are single-path transmembrane proteins that can homodimerize and heteroligomerize. Their extracellular domain is composed of a tandem of two immunoglobulin-like domains (Ig) involved in ligand-binding and two fibronectin III (FNIII) repeats. The transmembrane domain is followed by the cytoplasmic tail, wherein lies PTK activity [
86]. Growth-arrest-specific 6 (Gas6) and protein S (ProS), the two natural ligands of TAM receptors, have a similar domain organization: an
N-terminal region containing 11 g-carboxyglutaminic acid residues (Gla), followed by four EGF-like domains, and a
C-terminal region composed of two globular laminin G-like (LG) domains [
83,
87]. Contrary to TIM receptors, TAM receptors do not bind directly to apoptotic cells, but indirectly, through a process that requires the presence of Gas6/ProS, which function as bridging molecules. Their γ-carboxylated Gla domain interacts with PtdSer, while the LG domains bind to the Ig-like domains of TAM receptors [
88,
89]. DENV and WNV binding to TAM receptors occurs only in the presence of TAM ligands Gas6/ProS, which is akin to the mechanism of the recognition of apoptotic bodies (
Figure 2). Indeed, we have also shown that mutations of conserved amino acids in the Ig-like domain involved in ligand binding abolish infection promoted by TAM receptor expression. The same has been noted with Gla-domain-deleted Gas6 [
34]. These data argue for a tripartite model, whereby TAM ligands bind to PtdSer associated with DENV particles and bridge virions to TAM receptors. TYRO3 and AXL ectopic expression enhances infection by all DENV serotypes, as well as by the related WNV and YFV. Furthermore, infection of primary human cells or cell lines that are susceptible to flaviviruses, such as astrocytes or epithelial cell lines, relies on AXL endogenous expression, because antibodies against this receptor strongly block DENV infection [
34].
Figure 2.
Hypothetical model for flavivirus recognition by TIM and TAM receptors. Phosphatidylserine (PtdSer) is expressed at the viral membrane and its recognition by TIM and TAM receptors occurs through a bimodal mechanism. The MILIBS pocket within the IgV domain of TIM receptors directly interacts with PtdSer. In contrast, the recognition of viral particles by TAM receptors is indirect and requires the presence of a TAM ligand, Gas6 or ProS. These molecules recognize both the virus-associated PtdSer via their Gla domain, and the TAM receptors through their LG domains and, thus, act as bridging factors.
Figure 2.
Hypothetical model for flavivirus recognition by TIM and TAM receptors. Phosphatidylserine (PtdSer) is expressed at the viral membrane and its recognition by TIM and TAM receptors occurs through a bimodal mechanism. The MILIBS pocket within the IgV domain of TIM receptors directly interacts with PtdSer. In contrast, the recognition of viral particles by TAM receptors is indirect and requires the presence of a TAM ligand, Gas6 or ProS. These molecules recognize both the virus-associated PtdSer via their Gla domain, and the TAM receptors through their LG domains and, thus, act as bridging factors.